Tyrosinemia type I is an autosomal recessive metabolic disease caused by deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). Its main clinical features include progressive liver failure, renal tubular damage, neurologic crisis and the development of liver cancer. Biochemically the disease is characterized by the accumulation of toxic metabolites such as succinyl acetone, but also multiple secondary abnormalities in liver metabolism such as decreased tyrosine amino transferase (TAT) and elevated alpha-fetoprotein (AFP). The mortality rate is high despite dietary therapy and death usually occurs in childhood unless liver transplantation is performed. However, an adequate animal model in which to test therapeutic strategies and to study the disease pathophysiology is not available. We have used homologous recombination in embryonic stem cells to disrupt exon 5 of the murine FAH gene and have created mice heterozygous for this FAHexon5 mutation. In this application we propose to carry out the phenotypic and biochemical characterization of animals homozygous for FAHexon5. Should the new mouse strain prove to not represent an adequate model of the human mutations into the FAHexon5 background. Mutations in human tyrosinemia I patients will be identified and characterized for this purpose. We will use the FAH deficient mice to test dietary and pharmacological treatments for the disorders. We will focus our efforts on using inhibitors of homogentisic acid oxidase to refuse the production of toxic metabolites and to ameliorate the cellular damage caused by the disease.